PROJECT SUMMARY This is an initial submission of a K23 application by Dr. Charles Ginsberg, under the mentorship of Dr. Joachim Ix at the University of California San Diego (UCSD). Through this proposal Dr. Ginsberg intends to establish himself as an independent investigator studying the chronic kidney disease-mineral bone disorder (CKD-MBD). Candidate: Dr. Ginsberg's training objectives in this proposal include; 1)become proficient in the performance of bone biopsies, 2)the interpretation of bone histomorphometry and 3)learn the necessary skills to develop a research team and conduct clinical trials. Dr. Ginsberg will accomplish these objectives through mentorship, coursework, and participation in workshops and steering committees. He has assembled a multidisciplinary team of scientists including his primary mentor Dr. Joachim Ix, an expert in the CKD-MBD, Dr. Florin Vaida, an expert biostatistician at UCSD, and Dr. Isidro Salusky a leader in bone biopsy performance and interpretation. Research: Vitamin D deficiency is common among Americans and is known to lead to osteomalacia, rickets, and fractures. Serum 25-hydroxyvitamin D [25(OH)D], the recommended clinical parameter to assess for vitamin D deficiency, is flawed as there is conflicting evidence of association between 25(OH)D with bone density and fracture risk. Dr. Ginsberg hypothesizes that the weakness of 25(OH)D as a marker for bone health is, in part, due to variability in vitamin D binding protein (DBP). In Dr. Ginsberg's preliminary work he demonstrated that the ratio of 24,25-dihydroxyvitamin D to 25(OH)D [the vitamin D metabolite ratio (VMR)] is a superior marker of fracture risk in older adults, compared to 25(OH)D alone. The VMR is hypothesized to be a marker of vitamin D status that is independent of DBP concentrations. In Aim 1, Dr. Ginsberg will evaluate the relationship between 25(OH)D, other vitamin D metabolites, and the VMR with serum DBP concentrations among 1,142 older adults in the Health, Aging and Body Composition (Health ABC) Study; an observational cohort comprised of individuals with and without CKD. This will establish if the VMR is in fact independent of differences in DBP concentrations. In Aim 2, Dr. Ginsberg will evaluate the associations between 25(OH)D, other vitamin D metabolites, and the VMR with longitudinal change in bone density in the Health ABC Study and will determine if accounting for differences in DBP influences these relationships. In Aim 3, Dr. Ginsberg will evaluate the associations of 25(OH)D, other vitamin D metabolites, and the VMR with the degree of unmineralized bone in patients with CKD undergoing bone biopsies. This will provide a direct pathological correlate of bone disease and will determine the degree to which these relationships are influenced by DBP concentrations. This will not only allow for a better understanding of the variability in bone pathology seen across the spectrum of CKD but will also identify valuable biomarkers of the CKD-MBD and may ultimately provide a more rational approach to measurement and treatment of vitamin D insufficiency.